Biobeneficial coating compositions and methods of making and using thereof

ABSTRACT

A biobeneficial coating composition for coating an implantable device, such as a drug eluting stent, a method of coating the device with the composition, an implantable device coated with the composition, and a method of treating a disorder are provided.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 12/874,895 filed on Sep. 2, 2010, which is a divisional applicationof U.S. application Ser. No. 10/723,043 filed on Nov. 26, 2003, now U.S.Pat. No. 7,807,722, the teachings of which are incorporated by referenceherein in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention generally relates to a polymeric coating composition forcoating an implantable device, such as a stent.

2. Description of the Background

Polymeric coatings have been used for coating stents. One of thecommercially available polymer coated products is stents manufactured byBoston Scientific. For example, U.S. Pat. Nos. 5,869,127; 6,099,563;6,179,817; and 6,197,051, assigned to Boston Scientific Corporation,describe various compositions for coating medical devices. Thesecompositions provide to stents described therein an enhancedbiocompatibility and may optionally include a bioactive agent. U.S. Pat.No. 6,231,590 to Scimed Life Systems, Inc., describes a coatingcomposition which includes a bioactive agent, a collagenous material, ora collagenous coating optionally containing or coated with otherbioactive agents.

The nature of the coating polymers plays an important role in definingthe surface properties of a coating. For example, very a low T_(g),amorphous coating material induces unacceptable rheological behaviorupon mechanical perturbation such as crimping, balloon expansion, etc.On the other hand, a high T_(g), or highly crystalline coating materialintroduces brittle fracture in the high strain areas of the stentpattern.

A current paradigm in biomaterials is the control of protein adsorptionon the implant surface. Uncontrolled protein adsorption, leading tomixed layer of partially denatured proteins, is a hallmark of currentbiomaterials when implanted. Such a surface presents different cellbinding sites from adsorbed plasma proteins such as fibrogen andimmunogloblulin G. Platelets and inflammatory cells such asmonocyte/macrophages and neutrophils adhere to these surfaces.Unfavorable events can be controlled by the use of non-fouling surfaces.These are materials, which absorb little or no protein, primarily due totheir hydrophilic surface properties.

Another limitation of current drug eluting stents stems from the factthat the stent is a foreign body. Use of drug eluting stents has provedsuccessful by use of controlled release of anti-proliferative drugs tocontrol restenosis. However, drug eluting stents still have a small, butmeasurable, incidence of sub-acute thrombosis. Moreover, drug elutingstents have not driven restenosis to zero levels, especially in morechallenging patient subsets such as diabetics or patients with smallvessels, and/or long, diffuse lesions. A biomaterials-based strategy forfurther improving the outcome of drug eluting stents is by the use ofbiobeneficial materials or surfaces in stent coatings. A biobeneficialmaterial is one which enhances the biocompatibility of a device by beingnon-fouling, hemocompatible, actively non-thrombogenic, oranti-inflammatory, all without depending on the release of apharmaceutically active agent.

U.S. application No. 2002/0107330 to Pinchuk, et al., describes acomposition containing a blend ofpolystyrene-polyisobutylene-polystyrene copolymer and paclitaxel invarious ratios. The composition, when coated onto an implantable device,may be covered with a barrier layer of, or blended with, a polymer ormaterial such as polyethylene oxide or hyaluronic acid (see alsoPinchuk, et al., “Polyisobutylene-based Thermoplastic Elastomers forUltra Long-Term Implant Applications,” Society for Biomaterials, 6^(th)World Biomaterials Congress Transactions, 2000, #1452; Drachman D E, etal., J. Amer. Coll Cardiology, 36(7):2325-2332 (2000); Pinchuk, J.Biomater. Sci. Polymer edn., 6(3):225-267 (1994)). However, it is wellknown in the art that many biobeneficial materials such as polyethyleneoxide or hyaluronic acid are water-soluble and can be leached out of thecomposition such that the coating may lose biobeneficiality.

The present invention addresses such problems by providing a coatingcomposition for coating implantable devices.

SUMMARY OF THE INVENTION

It is provided a biobeneficial composition for coating an implantabledevice or delivery of a bioactive agent. The biobeneficial compositioncomprises a first block copolymer and a biobeneficial polymer.Alternatively, the biobeneficial polymer may comprise a first blockcopolymer and a second block copolymer, the second block copolymercomprising a biobeneficial component and another component, which iseither water soluble or miscible with the first block copolymer. Thefirst block copolymer has a block with a T_(g) below about bodytemperature and another block that has a T_(g) above about bodytemperature or has considerable crystallinity with a T_(m) above aboutbody temperature. As used herein, the term “body temperature” refers tothe normal body temperature of a human, which is about 37° C., e.g.,about 36° C. to 37.5° C. The block with a Tg below about bodytemperature has an amorphous structure and is elastomeric. Thecomposition described herein is elastomeric but very oxidationresistant. The high T_(g) block renders the first block copolymer notvery permeable, or accessible, to reactive oxygenated species. Theelastomeric, low T_(g) block can be oxidation resistant. The compositiondescribed herein may further include a bioactive agent.

The composition described herein can be used for coating an implantabledevice such as a stent or for controlled delivery of a bioactive agent.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a scheme of forming a conjugate ofpolystyrene-polyisobutylene-polystyrene block copolymer withpoly(ethylene glycol) (PEG).

FIG. 2 is a scheme of forming a conjugate ofpolystyrene-polyisobutylene-polystyrene block copolymer with4-amino-2,2,6,6-tetramethylpiperidine-1-oxide (4-amino-TEMPO).

DETAILED DESCRIPTION Biobeneficial Compositions

A biobeneficial composition for coating an implantable device ordelivery of a bioactive agent is provided. The biobeneficial compositioncomprises a first block copolymer and a biobeneficial polymer.Alternatively, the biobeneficial composition may comprise a first blockcopolymer and a second block copolymer, the second block copolymercomprising a biobeneficial component and another component that iseither water insoluble or miscible with the first block copolymer. Thefirst block copolymer has a block with a T_(g) below about bodytemperature and another block with a T_(g) above about body temperatureor that has considerable crystallinity with a T_(m) above about bodytemperature. The block with a T_(g) below about body temperature has anamorphous structure and is elastomeric. Functionally, the elastomeric,low T_(g) block provides for flexibility, and the block with T_(g) orT_(m) above about body temperature acts as a virtual crosslink. Thecomposition described herein may further include a bioactive agent.

T_(g) as used herein generally refers to the temperature at which theamorphous domains of a polymer change from a brittle vitreous state to aplastic state at atmospheric pressure. In other words, T_(g) correspondsto the temperature where the onset of segmental motion in the chains ofthe polymer occurs, and it is discernible in aheat-capacity-versus-temperature graph for a polymer. When an amorphousor semicrystalline polymer is heated, its coefficient of expansion andheat capacity both increase as the temperature rises, indicatingincreased molecular motion. As the temperature rises, the sample'sactual molecular volume remains constant. Therefore, a highercoefficient of expansion points to a free volume increase of the systemand increased freedom of movement for the molecules. The increasing heatcapacity corresponds to increasing heat dissipation through movement.

T_(g) of a given polymer can be dependent on the heating rate and can beinfluenced by the thermal history of the polymer. Furthermore, polymerchemical structure heavily influences T_(g) by affecting polymermobility. Generally, flexible main-chain components lower T_(g) andbulky side groups raise T_(g). Similarly, increasing flexible-side-grouplength lowers T_(g) and increasing main-chain polarity increases T_(g).Additionally, the presence of crosslinks can increase the observed T_(g)for a given polymer, and the presence of a drug or therapeutic agent canalter the T_(g) of a polymer due to plasticization effects. Themagnitude of these plasticization effects depends on the miscibility andcompatibility of the drug and polymer and the loading of drug in thepolymer.

As used herein, the term “biobeneficial” refers to an attribute of amaterial that increases the biocompatibility and/or bio-responses of acoating on an implantable device.

The term “water insoluble” as used herein refers to an attribute of amaterial having a quality of being insoluble as understood by one ofordinary skill in the art. One indication of a material's beinginsoluble is the material having a solubility in water less than orequal to 1% (w/w) or 10 mg/gm at 37° C. and 1 atm.

The composition described herein is elastomeric, but very oxidationresistant. The high T_(g) block renders the first block copolymer notvery permeable, or accessible, to reactive oxygenated species. Theelastomeric, low T_(g) block can be oxidation resistant. For example,the elastomeric, low T_(g) block can be a polyisobutyl block, which isoxidation resistant because every other carbon is a tertiary carbon.Free radicals and oxidants can attach and oxidize the CH₂ moieties ofthe polyisobutyl block forming hydroxyl and carbonyl groups. However,due to the alternating secondary and tertiary carbons, no secondarycarbons are adjacent, making it impossible to form carbon-carbon doublebonds in the polymer backbone. Consequently, the backbone of thepolyisobutyl block will remain intact.

The composition described herein can be used for coating an implantabledevice such as a stent or for controlled delivery of a bioactive agent.The composition can also be used to make an implantable medical device.

In accordance with one aspect of the invention, the compositiondisclosed herein comprises a conjugate of a first block copolymercomprising at least one elastomeric block having a T_(g) below aboutbody temperature and another block having a Tg or Tm above about bodytemperature with a biobeneficial polymer. The block having a T_(g) aboveabout body temperature has a structure of Formula I and the elastomericblock having a T_(g) below about body temperature has a structure ofFormula II:

wherein R₁, R₂, R₃ and R₄ are independently hydrogen, phenyl, methyl,ethyl, carboxylate, acrylate, or methacrylate provided that R₁, R₂, R₃and R₄ cannot be all hydrogen; R₅ and R₇ or R₆ and R₈ are independentlymethyl, ethyl, propyl, butyl, benzyl, or phenyl; and R₆ and R₈ or R₅ andR₇ are independently hydrogen, methyl, ethyl, propyl, benzyl, or phenyl.The high Tg block can be polystyrene, poly(methyl methacrylate),poly(ethyl methacrylate), poly(propyl methacrylate), poly(isopropylmethacrylate), poly(4-methylstyrene), poly(alpha-methyl styrene),poly(benzyl methacrylate), poly(tert-butyl methacrylate),poly(chloro-styrene), or poly(bromo-styrene). Useful elastomeric, lowT_(g) block includes, poly(isobutylene), poly(n-butyl methacrylate),poly(n-hexyl methacrylate), poly(n-octyl methacrylate), poly(n-laurylmethacrylate), poly(2-ethylhexyl methacrylate), and poly(octadecylmethacrylate). The first block copolymer can be an A-B diblock copolymeror A-B-A or B-A-B triblock copolymer.

In one embodiment, the first block copolymer has the following structureof formula III:

wherein m and n are positive integers.

In a further embodiment, the conjugate can have a structure of thefollowing:

wherein m and n are positive integers; or

wherein m and n are positive integers.

Representative biobeneficial polymers include, but are not limited to,poly(ethylene glycol) (PEG), polypropylene glycol), PLURONIC™surfactants which are block copolymers based on ethylene oxide andpropylene oxide, poly(tetramethylene glycol), hydroxy functionalpoly(vinyl pyrrolidone), polyalkylene oxide, dextran, dextrin, sodiumhyaluronate, hyaluronic acid, sulphonated poly(styrene), heparin,Elastin, Chitosan, poly(2-hydroxyethyl methacrylate),poly(3-hydroxypropyl methacrylamide), 4-amino-2,2′,6,6′-tetrapiperidineoxide, stable nitroxides, super oxide dimutase mimics, free radicalscavengers, and combination thereof. The biobeneficial can be conjugatedto the high T_(g) block of the block copolymer via a linkage, which canbe a direct covalent bond, hydrogen bond, ionic bond or chelate.Preferably, the linkage is covalent such as through an amino linkage, anester linkage, an ether linkage, a peptide linkage, an amide linkage, aurethane linkage, a carbonate linkage, via a carbon-carbon bond, ahydrazide linkage, a sulfonate linkage, a sulfone linkage, or a thiolether linkage. The biobeneficial polymer can be attached to the high Tgblock of the block copolymer via any method known in the art (see, forexample, Michael Smith, Organic Synthesis, 2^(nd) Edition, McGraw-Hill,2001).

As an example, PEG is attached topolystyrene-polyisobutylene-polystyrene (SIS) triblock copolymer viareductive amination as shown in FIG. 1. First, the SIS triblockcopolymer is subjected to acylation in the presence of a Lewis acidcatalyst such as AlCl₃. The acylated SIS triblock copolymer is thensubjected to reductive amination with commercially available mPEG-NH₂(available from vendors such as Nektar) in the presence of a reducingagent such as sodium cyanoborohydride, forming a SIS-PEG conjugate asshown in FIG. 1.

As a further example, a small molecule such as4-amino-2,2′,6,6′-tetrapiperidine oxide (4-amino-TEMPO) can be attachedto a SIS triblock copolymer as shown in FIG. 2. The SIS triblockcopolymer is first subjected to acylation in the presence of a Lewisacid such as AlCl₃. The acylated SIS triblock copolymer is thensubjected to reductive amination in the presence of sodiumcyanoborohydride to form a 4-amino-TEMPO derivatized SIS triblockcopolymer (FIG. 2).

In accordance with another aspect of the invention, the compositiondisclosed herein comprises a first block copolymer comprising a blockwith a T_(g) above about body temperature and an elastomeric block witha T_(g) below about body temperature and a second block copolymercomprising a biobeneficial component and another component which iswater insoluble or miscible with the first block copolymer, which isdescribed above. The component miscible with the first block copolymeris hydrophobic. Representative examples can includepolystyrene-polyisobutylene-polystyrene block copolymer (SIS),polystyrene, polyisobutylene, polycaprolactone (PCL), poly(L-lactide),poly(D,L-lactide), poly(lactides), polylactic acid (PLA),poly(lactide-co-glycolide), poly(glycolide), polyalkylene,polyfluoroalkylene, polyhydroxyalkanoate, poly(3-hydroxybutyrate),poly(4-hydroxybutyrate), poly(3-hydroxyvalerate),poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxyhexanoate),poly(4-hyroxyhexanoate), mid-chain polyhydroxyalkanoate,poly(trimethylene carbonate), poly(ortho ester), polyphosphazenes,poly(phosphoester), poly(tyrosine derivedarylates), poly(tyrosinederived carbonates). The water insoluble component of the secondcopolymer includes, for example, polydimethyloxanone (PDMS),polyvinylidene fluoride (PVDF), polyhexafluoropropylene (HFP),polydimethylsiloxane, poly(vinylidene fluoride-co-hexafluoropropylene)(PVDF-HFP), poly(vinylidene fluoride-co-chlorotrifluoroethylene)(PVDF-CTFE), poly(butyl methacrylate), poly(methyl methacrylate),poly(methacrylates), poly(vinyl acetate), poly(ethylene-co-vinylacetate), poly(ethylene-co-vinyl alcohol), poly(ester urethanes),poly(ether-urethanes), poly(carbonate-urethanes),poly(silicone-urethanes), poly(urea-urethanes) and a combinationthereof.

In one embodiment, the second block copolymer comprising a biobeneficialcomponent is SIS-PEG, polystyrene-PEG, polyisobutylene-PEG, PCL-PEG,PLA-PEG, PMMA-PEG, PDMS-PEG, PVDF-PEG, SIS-hyaluronic acid (HA),polystyrene-HA, polyisobutylene-HA, PCL-HA, PLA-HA, PMMA-HA, PVDF-HA,SIS-heparin, polystyrene-heparin, polyisobutylene-heparin, PCL-heparin,PLA-heparin, PMMA-heparin, or PVDF-heparin.

As used herein, a conjugate is formed by combining one material, e.g., apolymer, with one or more other materials, e.g., a polymer of differentnature, by ionic interaction, hydrogen bonding, or covalent bonding. Theconjugate can be, for example, a block copolymer, an adduct, ion pair,polyelectrolyte complex, or chelate.

Active Agents

In accordance with a further embodiment of the invention, thecomposition described herein may optionally include one or more activeagents. The active agent can be for inhibiting the activity of vascularsmooth muscle cells. More specifically, the active agent can be aimed atinhibiting abnormal or inappropriate migration and/or proliferation ofsmooth muscle cells for the inhibition of restenosis.

The active agent can also include any substance capable of exerting atherapeutic, prophylactic or diagnostic effect. For example, the activeagent can be for enhancing wound healing in a vascular site or improvingthe structural and elastic properties of the vascular site. Examples ofactive agents include antiproliferative substances such as actinomycinD, or derivatives and analogs thereof (manufactured by Sigma-Aldrich1001 West Saint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGENavailable from Merck). Synonyms of actinomycin D include dactinomycin,actinomycin IV, actinomycin I₁, actinomycin X₁, and actinomycin C₁. Theactive agent can also fall under the genus of antineoplastic,anti-inflammatory, antiplatelet, anticoagulant, antifibrin,antithrombin, antimitotic, antibiotic, antiallergic and antioxidantsubstances. Examples of such antineoplastics and/or antimitotics includepaclitaxel (e.g. TAXOL® by Bristol-Myers Squibb Co., Stamford, Conn.),docetaxel (e.g. Taxotere®, from Aventis S.A., Frankfurt, Germany)methotrexate, azathioprine, vincristine, vinblastine, fluorouracil,doxorubicin hydrochloride (e.g. Adriamycin® from Pharmacia & Upjohn,Peapack N.J.), and mitomycin (e.g. Mutamycin® from Bristol-Myers SquibbCo., Stamford, Conn.). Examples of such antiplatelets, anticoagulants,antifibrin, and antithrombins include sodium heparin, low molecularweight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost,prostacyclin and prostacyclin analogues, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody,recombinant hirudin, and thrombin inhibitors such as Angiomax ä (Biogen,Inc., Cambridge, Mass.). Examples of such cytostatic orantiproliferative agents include angiopeptin, angiotensin convertingenzyme inhibitors such as captopril (e.g. Capoten® and Capozide® fromBristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril(e.g. Prinivil® and Prinzide® from Merck & Co., Inc., WhitehouseStation, N.J.); calcium channel blockers (such as nifedipine),colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega3-fatty acid), histamine antagonists, lovastatin (an inhibitor ofHMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor® fromMerck & Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies(such as those specific for Platelet-Derived Growth Factor (PDGF)receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandininhibitors, suramin, serotonin blockers, steroids, thioproteaseinhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide. Anexample of an antiallergic agent is permirolast potassium. Othertherapeutic substances or agents which may be appropriate includealpha-interferon, and genetically engineered epithelial cells. Theforegoing substances are listed by way of example and are not meant tobe limiting. Other active agents which are currently available or thatmay be developed in the future are equally applicable. Such other activeagents include, for example, any anti-cancers, anti-genesis,antibiotics, anti-fungal agents and antibodies, proteins, peptides,anti-inflammatory agents, steroidal anti-inflammatory agents,antivirals, anticancer drugs, free radical scavengers, Everolimus,sirolimus, sirolimus derivatives, paclitaxel, estradiol, nitric oxidedonors, super oxide dismutases, super oxide dismutases mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,ABT-578, clobetasol, cytostatic agents, and a combination thereof.

The dosage or concentration of the active agent required to produce afavorable therapeutic effect should be less than the level at which theactive agent produces toxic effects and greater than the minimum levelat which therapeutic results are obtained. The dosage or concentrationof the active agent required to inhibit the desired cellular activity ofthe vascular region can depend upon factors such as the particularcircumstances of the patient; the nature of the trauma; the nature ofthe therapy desired; the time over which the administered ingredientresides at the vascular site; and if other active agents are employed,the nature and type of those agents or combinations of those agents.Therapeutic effective dosages can be determined empirically in vivo, forexample by infusing vessels from suitable animal model systems and usingimmunohistochemical, fluorescent or electron microscopy methods todetect the agent and its effects, or by conducting suitable in vitrostudies. Standard pharmacological test procedures to determine dosagesare understood by one of ordinary skill in the art.

Examples of radiopaque elements include, but are not limited to, gold,tantalum, and platinum. An example of a radioactive isotope is ³²P.Sufficient amounts of such substances may be dispersed in thecomposition such that the substances are not present in the compositionas agglomerates or flocs.

Method of Coating a Device

The composition described herein can be coated on an implantable devicesuch as a stent by spray coating or any other coating process availablein the art. Generally, the coating involves dissolving or suspending thecomposition, or one or more components thereof, in a solvent or solventmixture to form a solution, suspension, or dispersion of the compositionor one or more components thereof, applying the solution or suspensionto an implantable device, and removing the solvent or solvent mixture toform a coating or a layer of coating. Suspensions or dispersions of thecomposition described herein can be in the form of latex or emulsion ofmicroparticles having a size between 1 nanometer and 100 microns,preferably between 1 nanometer and 10 microns. Heat and/or pressuretreatment can be applied to any of the steps involved herein. Inaddition, if desirable, the coating described here can be subjected tofurther heat and/or pressure treatment. Some additional exemplaryprocesses of coating an implantable device that may be used to form acoating on an implantable using the composition described herein aredescribed in, for example, Lambert T L, et al. Circulation, 1994; 90:1003-1011; Hwang C W, et al. Circulation, 2001; 104: 600-605; Van derGiessen W J, et al. Circulation, 1996; 94: 1690-1697; Lincoff A M, etal. J Am Coll Cardiol 1997; 29: 808-816; Grube E. et al, J AmericanCollege Cardiology Meeting, Mar. 6, 2002, ACCIS2002, poster 1174-15;Grube E, et al, Circulation, 2003, 107: 1, 38-42; Bullesfeld L, et al. ZKardiol, 2003, 92: 10, 825-832; and Tanabe K, et al. Circulation 2003,107: 4, 559-64.

The composition can be coated onto the implantable device in the form ofa single layer of coating or components of the composition can be coatedonto the device in the form of separate layers of coating.

As used herein, the term “solvent” refers to a liquid substance orcomposition that is compatible with the polymer and is capable ofdissolving or suspending the polymeric composition or one or morecomponents thereof at a desired concentration. Representative examplesof solvents include chloroform, acetone, water (buffered saline),dimethylsulfoxide (DMSO), propylene glycol monomethyl ether (PM,)iso-propylalcohol (IPA), n-propyl alcohol, methanol, ethanol,tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl acetamide(DMAC), benzene, toluene, xylene, hexane, cyclohexane, heptane, octane,nonan, decane, decalin, ethyl acetate, butyl acetate, isobutyl acetate,isopropyl acetate, butanol, diacetone alcohol, benzyl alcohol,2-butanone, cyclohexanone, dioxane, methylene chloride, carbontetrachloride, tetrachloroethylene, tetrachloro ethane, chlorobenzene,1,1,1-trichloroethane, 1,1,2-trichloroethane, formamide,hexafluoroisopropanol, 1,1,1-trifluoroethanol, and hexamethylphosphoramide and a combination thereof.

Examples of such implantable devices include self-expandable stents,balloon-expandable stents, stent-grafts, grafts (e.g., aortic grafts),artificial heart valves, cerebrospinal fluid shunts, pacemakerelectrodes, and endocardial leads (e.g., FINELINE and ENDOTAK, availablefrom Guidant Corporation, Santa Clara, Calif.). The underlying structureof the device can be of virtually any design. The device can be made ofa metallic material or an alloy such as, but not limited to, cobaltchromium alloy (ELGILOY), stainless steel (316L), high nitrogenstainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, “MP35N,”“MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from Standard Press Steel Co.,Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Devices made frombioabsorbable or biostable polymers could also be used with theembodiments of the present invention. In one embodiment, the implantabledevice is a stent.

The compositions described herein can be coated onto a bare metallic orpolymeric implantable device or on top of a drug eluting coating on theimplantable device.

Method of Use

In accordance with embodiments of the invention, a composition in thevarious embodiments as described above can be applied to an implantabledevice or prosthesis, e.g., a stent. For compositions including one ormore active agents, the agent will remain on the medical device such asa stent during delivery and expansion of the device, and released at adesired rate and for a predetermined duration of time at theimplantation site. Preferably, the medical device is a stent. A stenthaving the above-described coating is useful for a variety of medicalprocedures, including, by way of example, treatment of obstructionscaused by tumors in bile ducts, esophagus, trachea/bronchi and otherbiological passageways. A stent having the above-described coating isparticularly useful for treating occluded regions of blood vesselscaused by atherosclerosis, or abnormal or inappropriate migration andproliferation of smooth muscle cells, thrombosis, and restenosis. Stentsmay be placed in a wide variety of blood vessels, both arteries andveins. Representative examples of sites include the iliac, renal, andcoronary arteries.

The implantable device comprising a coating described herein can be usedto treat an animal having a condition or disorder that requires atreatment. Such an animal can be treated by, for example, implanting adevice described herein in the animal. Preferably, the animal is a humanbeing. Exemplary disorders or conditions that can be treated by themethod disclosed herein include, but not limited to, occlusiveatherosclerotic lesions in the coronary vasculature, neointimalhyperplasia in the coronary arteries, restenosis in the coronaryarteries, vulnerable plaques of the coronary arteries, atherosclerosisin the renal arteries, atherosclerosis in the carotid arteries,atherosclerosis in the neurovasculature, atherosclerosis in the iliacarteries, atherosclerosis in the femoral arteries, atherosclerosis inthe popliteal arteries, atherothrombosis, and occlusive tumors of theprostate, liver, or gastrointestinal tract.

EXAMPLES

The embodiments of the present invention will be illustrated by thefollowing set forth prophetic examples. All parameters and data are notto be construed to unduly limit the scope of the embodiments of theinvention.

Example 1 The Polymer of Formula IV as a Topcoat in a Drug Eluting StentCoating for the Controlled Release of Paclitaxel from a Stent

A first composition is prepared by mixing the following components:

(a) 2.0 mass % of poly(n-butyl methacrylate) (PBMA), and

(b) the balance, a 50/50 blend by weight of acetone and cyclohexanone.

The first composition is applied onto the surface of bare 12 mm smallVISION™ stent (available from Guidant Corporation). Coating is sprayedand dried to form a primer layer. A spray coater is used having a 0.014round nozzle maintained at about body temperature with a feed pressure2.5 psi (0.17 atm) and an atomization pressure of about 15 psi (1.02atm). Coating is applied at 20 μg per pass, in between which the stentis dried for 10 seconds in a flowing air stream at 50 C. Approximately110 μg of wet coating is applied. The stents are baked at 50 C for onehour, yielding a primer layer composed of approximately 100 μg of PBMA.

A drug reservoir layer is applied onto the primer layer, using the samespraying technique, equipment, and formulation used for the applying theprimer. A second composition is prepared by mixing the followingcomponents:

(a) 2.0 mass % of the polymer of formula III,

(b) 0.67 mass % of paclitaxel, and

(c) the balance, a 50/50 blend of chloroform and 1,1,2-trichloroethane.

In this case approximately 220 μg of wet coating is applied, followed bydrying, e.g., baking at 50 C for about one hour, yielding about 200 μgof drug-polymer reservoir layer. A polymer of the current invention isused as a topcoat layer. Starting with the same polymer of Formula IIIused in the drug reservoir, grafting of PEG is carried out using anamino-terminated mPEG of molecular weight of 3400 Daltons. Enough PEGderivative is conjugated so that the final composition is 20% by weightPEG. Using this composition, namely:

(a) 2.0 mass % of (IV) as described above, and

(b) the balance, a 50/50 blend of chloroform and 1,1,2-trichloroethane.

This composition can be applied onto the drug reservoir layer to form atopcoat layer. Using the same spraying technique and equipment used forapplying the drug reservoir layer. Approximately 120 μg of wet topcoatis applied followed by baking at 50 C for one hour, yielding a 100 μgtopcoat layer of Formula IV to act as a biobeneficial topcoat.

Example 2 The Polymer of Formula IV is Used as a Matrix in a DrugEluting Stent Coating for the Controlled Release of Paclitaxel from aStent

A first composition is prepared by mixing the following components:

(a) 2.0 mass % of poly(n-butyl methacrylate) (PBMA), and

(b) the balance, a 50/50 blend by weight of acetone and cyclohexanone.

The first composition is applied onto the surface of bare 12 mm smallVISION™ stent (available from Guidant Corporation). Coating is sprayedand dried to form a primer layer. A spray coater is used having a 0.014round nozzle maintained at about body temperature with a feed pressure2.5 psi (0.17 atm) and an atomization pressure of about 15 psi (1.02atm). Coating is applied at 20 μg per pass, in between which the stentis dried for 10 seconds in a flowing air stream at 50 C. Approximately110 μg of wet coating was applied. The stents are baked at 50 C for onehour, yielding a primer layer composed of approximately 100 μg of PBMA.

A drug reservoir layer is applied onto the primer layer, using the samespraying technique, equipment, and formulation used for the applying theprimer. Starting with the same polymer of Formula III, grafting of PEGis carried out using an amino-terminated mPEG of molecular weight of 550Daltons. Enough PEG derivative is conjugated so that the finalcomposition is 5% by weight PEG. Using this composition, namely:

(a) 2.0 mass % of (IV) as described above,

(b) 0.5 mass % of paclitaxel, and

(c) the balance, a 50/50 blend of chloroform and 1,1,2-trichloroethane.

This composition can be applied onto the primer layer to form a drugreservoir layer. Using the same spraying technique and equipment usedfor applying the drug reservoir layer. Approximately 280 μg of wet isapplied followed by baking at 50° C. for one hour, yielding a 250 μgreservoir layer of the polymer of Formula IV to act as a reservoirpolymer with higher drug permeability than the polymer of formula III.

Example 3 The Polymer of Formula IV as a Topcoat in a Drug Eluting StentCoating for the Controlled Release of Everolimus from a Stent

A first composition is prepared by mixing the following components:

(a) 2.0 mass % of poly(ethylene-co-vinyl alcohol) (EVAL E-151A), and

(b) the balance, a 70/30 blend by weight of dimethylacetamide andtetrahydrofuran.

The first composition is applied onto the surface of bare 12 mm smallVISION™ stent (available from Guidant Corporation). Coating is sprayedand dried to form a primer layer. A spray coater is used having a 0.014round nozzle maintained at about body temperature with a feed pressure2.5 psi (0.17 atm) and an atomization pressure of about 15 psi (1.02atm). Coating is applied at 10 μg per pass, in between which the stentis dried for 10 seconds in a flowing air stream at 50 C. Approximately120 μg of wet coating was applied. The stents are baked at 140 C for onehour, yielding a primer layer composed of approximately 100 μg of EVAL.A drug reservoir layer is applied onto the primer layer, using the samespraying technique, equipment, and polymer as used in applying theprimer:

(a) 2.0 mass % of EVAL E-151A as described above,

(b) 0.67 mass % of everolimus, and

(c) the balance, a 70/30 blend by weight of dimethylacetamide andtetrahydrofuran.

This composition can be applied onto the primer layer to form a drugreservoir layer. Using the same spraying technique and equipment usedfor applying the drug reservoir layer. Approximately 240 μg of wet isapplied followed by baking at 80 C for 30 minutes, yielding a 223 μgreservoir layer. A polymer of the current invention is used as a topcoatlayer. Starting with the same polymer of Formula III used in the drugreservoir, grafting of PEG is carried out using an amino-terminated mPEGof molecular weight of 500 Daltons. Enough PEG derivative is conjugatedso that the final composition is 20% by weight PEG. Using thiscomposition, namely:

(a) 2.0 mass % of (IV) as described above, and

(b) the balance, a 50/50 blend of chloroform and 1,1,2-trichloroethane

This composition can be applied onto the drug reservoir layer to form atopcoat layer. Using the same spraying technique and equipment used forapplying the drug reservoir layer. Approximately 120 μg of wet topcoatis applied followed by baking at 50 C for one hour, yielding a 100 μgtopcoat layer of Formula IV to act as a biobeneficial topcoat.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

The embodiments of the present invention also include the following:

1. A method of treating a disorder in a subject by implanting in thesubject an implantable device, wherein the implantable device comprisinga coating which comprises a composition, wherein the compositioncomprises

(1) a first block copolymer comprising a block having a glass transitiontemperature (T_(g)) below about body temperature and a second blockhaving a T_(g) or a melting temperature (T_(m)) above about bodytemperature, and

(2) a material selected from the group consisting of a biobeneficialpolymer capable of forming a conjugate with the first block copolymer, asecond block copolymer and combination thereof, wherein the second blockcopolymer comprising

-   -   (i) a biobeneficial component; and    -   (ii) a component selected from the group consisting of        components miscible with the first block copolymer and        components insoluble in water.

2. The method of embodiment 1, wherein the block having a T_(g) aboveabout body temperature has a structure of Formula I and the block havinga T_(g) below about body temperature has a structure of Formula II:

wherein R₁, R₂, R₃ and R₄ are independently hydrogen, phenyl, methyl,ethyl, acrylate, or methacrylate, with the proviso that R₁, R₂, R₃ andR₄ can not all be hydrogen;

wherein R₅ and R₇ are independently methyl, ethyl, propyl, butyl,benzyl, or phenyl; and

wherein R₆ and R₈ are independently hydrogen, methyl, ethyl, propyl,benzyl, or phenyl.

3. The method of embodiment 1, wherein the first block copolymer has thefollowing structure:

4. The method of embodiment 1, wherein the biobeneficial agent iscovalently attached to the first block copolymer via a chemical linkage.

5. The method of embodiment 3, wherein the biobeneficial agent iscovalently attached to the phenyl ring of the structure of Formula III.

6. The method of embodiment 5, wherein the biobeneficial polymer isselected from the group consisting of poly(ethylene glycol),poly(propylene glycol), PLURONIC™ surfactants, poly(tetramethyleneglycol), hydroxy functional poly(vinyl pyrrolidone), dextran, dextrin,sodium hyaluronate, hyaluronic acid, heparin, Elastin, Chitosan,poly(2-hydroxyethyl methacrylate), sulphonated poly(styrene),poly(3-hydroxypropyl methacrylamide), 4-amino-2,2′,6,6′-tetrapiperidineoxide, stable nitroxides, super oxide dimutase mimics, free radicalscavengers and combinations thereof.

7. The method of embodiment 6, wherein the conjugate has the structureof Formula IV:

8. The method of embodiment 6, wherein the conjugate has the structureof Formula V:

9. The method of embodiment 1, wherein the component of the second blockcopolymer miscible with the first block copolymer is a hydrophobicmaterial.

10. The method of embodiment 1, wherein the second block copolymer isselected from the group consisting ofpolystyrene-polyisobutylene-polystyrene block copolymer (SIS),polystyrene, polyisobutylene, polycaprolactone (PCL), poly(L-lactide),poly(D,L-lactide), poly(lactides), poly(lactide-co-glycolide),poly(glycolide), polylactic acid (PLA), polyalkylene,polyfluoroalkylene, polyhydroxyalkanoate, poly(3-hydroxybutyrate),poly(4-hydroxybutyrate), poly(3-hydroxyvalerate),poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxyhexanoate),poly(4-hydroxyhexanoate), mid chain polyhydroxyalkanoate,poly(trimethylene carbonate), poly(ortho ester), polyphosphazenes,poly(phosphoester), poly(tyrosine derived arylates), poly(tyrosinederived carbonates), and a combination thereof.

11. The method of embodiment 1, wherein the water insoluble component isselected from the group consisting of polydimethyloxanone (PDMS),polyvinylidene fluoride (PVDF), polyhexafluoropropylene (HFP),polydimethylsiloxane, poly(vinylidene fluoride-co-hexafluoropropylene)(PVDF-HFP), poly(vinylidene fluoride-co-chlorotrifluoroethylene)(PVDF-CTFE), poly(butyl methacrylate), poly(methyl methacrylate),poly(methacrylates), poly(vinyl acetate), poly(ethylene-co-vinylacetate), poly(ethylene-co-vinyl alcohol), poly(ester urethanes),poly(ether-urethanes), poly(carbonate-urethanes),poly(silicone-urethanes), and poly(urea-urethanes), and a combinationthereof.

12. The method of embodiment 1, wherein the biobeneficial component ofthe second block copolymer is selected from the group consisting ofpoly(ethylene glycol), poly(propylene glycol), PLURONIC™ surfactants,poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone),dextran, dextrin, sodium hyaluronate, hyaluronic acid, heparin, Elastin,Chitosan, poly(2-hydroxyethyl methacrylate), sulphonated poly(styrene),poly(3-hydroxypropyl methacrylamide), 4-amino-2,2′,6,6′-tetrapiperidineoxide, stable nitroxides, super oxide dimutase mimics, free radicalscavengers and combinations thereof.

13. The method of embodiment 1 wherein the second block copolymer isselected from the group consisting of SIS-PEG, polystyrene-PEG,polyisobutylene-PEG, PCL-PEG, PLA-PEG, PDMS-PEG, PVDF-PEG,SIS-hyaluronic acid (HA), polystyrene-HA, polyisobutylene-HA, PCL-HA,PLA-HA, PMMA-HA, PVDF-HA, SIS-heparin, polystyrene-heparin,polyisobutylene-heparin, PCL-heparin, PLA-heparin, PMMA-heparin, andPVDF-heparin.

14. The method of embodiment 1, wherein the composition furthercomprises a bioactive agent.

15. The method of embodiment 14, wherein the bioactive agent is selectedfrom the group consisting of proteins, peptides, anti-inflammatoryagents, antivirals, anticancer drugs, anticoagulant agents, free radicalscavengers, and a combination thereof.

16. The method of embodiment 14, wherein the bioactive agent is selectedfrom the group consisting of everolimus, sirolimus, sirolimusderivatives, paclitaxel, estradiol, steroidal anti-inflammatory agents,antibiotics, nitric oxide donors, super oxide dismutases, super oxidedismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin,40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,ABT-578, clobetasol, cytostatic agents, and a combination thereof.

17. The method of embodiment 1, wherein the implantable device is astent.

18. The method of embodiment 14, wherein the implantable device is astent.

19. The method of embodiment 18, wherein the implantable device is adrug eluting stent (DES).

20. The method of embodiment 19, wherein the subject is a human, andwherein disorder is selected from the group consisting of stenosis,occlusions of the arterial vasculature, and vulnerable plaque.

What is claimed is:
 1. A method of treating a disorder in a subject byimplanting in the subject an implantable device, wherein the implantabledevice comprising a coating which comprises a composition, wherein thecomposition comprises (1) a first block copolymer comprising a blockhaving a glass transition temperature (T_(g)) below about bodytemperature and a second block having a T_(g) or a melting temperature(T_(m)) above about body temperature, and (2) a second block copolymercomprising (i) a biobeneficial component; and (ii) a component selectedfrom the group consisting of components miscible with the first blockcopolymer and components insoluble in water.
 2. The method of claim 1,wherein the block having a T_(g) above about body temperature has astructure of Formula I and the block having a T_(g) below about bodytemperature has a structure of Formula II:

wherein R₁, R₂, R₃ and R₄ are independently hydrogen, phenyl, methyl,ethyl, acrylate, or methacrylate, with the proviso that R₁, R₂, R₃ andR₄ cannot all be hydrogen; wherein R₅ and R₇ are independently methyl,ethyl, propyl, butyl, benzyl, or phenyl; and wherein R₆ and R₈ areindependently hydrogen, methyl, ethyl, propyl, benzyl, or phenyl.
 3. Themethod of claim 1, wherein the first block copolymer has the followingstructure:


4. The method of claim 1, wherein the component of the second blockcopolymer miscible with the first block copolymer is a hydrophobicmaterial.
 5. The method of claim 1, wherein the component of the secondblock copolymer insoluble in water is selected from the group consistingof polydimethyloxanone (PDMS), polyvinylidene fluoride (PVDF),polyhexafluoropropylene (HFP), polydimethylsiloxane, poly(vinylidenefluoride-co-hexafluoropropylene) (PVDF-HFP), poly(vinylidenefluoride-co-chlorotrifluoroethylene) (PVDF-CTFE), poly(butylmethacrylate), poly(methyl methacrylate), poly(methacrylates),poly(vinyl acetate), poly(ethylene-co-vinyl acetate),poly(ethylene-co-vinyl alcohol), poly(ester urethanes),poly(ether-urethanes), poly(carbonate-urethanes),poly(silicone-urethanes), and poly(urea-urethanes), and a combinationthereof.
 6. The method of claim 1, wherein the biobeneficial componentof the second block copolymer is selected from the group consisting ofpoly(ethylene glycol), poly(propylene glycol), PLURONIC™ surfactants,poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone),dextran, dextrin, sodium hyaluronate, hyaluronic acid, heparin, Elastin,Chitosan, poly(2-hydroxyethyl methacrylate), sulphonated poly(styrene),poly(3-hydroxypropyl methacrylamide), 4-amino-2,2′,6,6′-tetrapiperidineoxide, stable nitroxides, super oxide dimutase mimics, free radicalscavengers and combinations thereof.
 7. The method of claim 1, whereinthe second block copolymer is selected from the group consisting ofpolystyrene-polyisobutylene-polystyrene block copolymer (SIS),polystyrene, polyisobutylene, polycaprolactone (PCL), poly(L-lactide),poly(D,L-lactide), poly(lactides), poly(lactide-co-glycolide),poly(glycolide), polylactic acid (PLA), polyalkylene,polyfluoroalkylene, polyhydroxyalkanoate, poly(3-hydroxybutyrate),poly(4-hydroxybutyrate), poly(3-hydroxyvalerate),poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxyhexanoate),poly(4-hydroxyhexanoate), mid chain polyhydroxyalkanoate,poly(trimethylene carbonate), poly(ortho ester), polyphosphazenes,poly(phosphoester), poly(tyrosine derived arylates), poly(tyrosinederived carbonates), and a combination thereof.
 8. The method of claim 1wherein the second block copolymer is selected from the group consistingof SIS-PEG, polystyrene-PEG, polyisobutylene-PEG, PCL-PEG, PLA-PEG,PDMS-PEG, PVDF-PEG, SIS-hyaluronic acid (HA), polystyrene-HA,polyisobutylene-HA, PCL-HA, PLA-HA, PMMA-HA, PVDF-HA, SIS-heparin,polystyrene-heparin, polyisobutylene-heparin, PCL-heparin, PLA-heparin,PMMA-heparin, and PVDF-heparin.
 9. The method of claim 1, wherein thecomposition further comprises a bioactive agent.
 10. The method of claim8, wherein the bioactive agent is selected from the group consisting ofproteins, peptides, anti-inflammatory agents, antivirals, anticancerdrugs, anticoagulant agents, free radical scavengers, and a combinationthereof.
 11. The method of claim 8, wherein the bioactive agent isselected from the group consisting of everolimus, sirolimus, sirolimusderivatives, paclitaxel, estradiol, steroidal anti-inflammatory agents,antibiotics, nitric oxide donors, super oxide dismutases, super oxidedismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin,40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,ABT-578, clobetasol, cytostatic agents, and a combination thereof. 12.The method of claim 1, wherein the implantable device is a stent. 13.The method of claim 9, wherein the implantable device is a stent. 14.The method of claim 13, wherein the implantable device is a drug elutingstent (DES).
 15. The method of claim 1, wherein the subject is a human,and wherein disorder is selected from the group consisting of stenosis,occlusions of the arterial vasculature, and vulnerable plaque.